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  • Follin, Per, 1953- (författare)
  • The primed neutrophil : a friend or a foe in inflammation
  • 1991
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Human neutrophils are the most abundant of the white blood cells in circulation and represent the first line of defense against invading microorganisms. With a membrane-bound enzyme system (the NADPH oxidase), these cells can generate reactive oxygen metabolites that serve efficiently in antimicrobial defense. Neutrophils are normally dormant in the circulation but may become primed; in that state they can produce an enhanced respiratory burst response upon activation and thereby strengthen the immune response.</p> <p>During bacterial infections, endogenous inflammatory mediators orbacterial products induce metabolic priming of neutrophils, which thenexpose an increased number of receptors to the peptide f-Meth-Leu-Phe(fMLP). There is, however, no correlation between the increased level ofrespiratory burst response and the level of receptor upregulation, indicating that post-receptor events in the activation sequence are also involved. Neutrophils isolated from an inflammatory focus were found tobe metabolically deactivated as far as the agonists NAP-1/IL 8 and C5awere concerned but primed in relation to tMLP. Further characterizationof exudated cells revealed that the mechanism of priming involves protein kinase C but not a rise in intracellular Ca2+ or a decreased inactivation rate of the oxidase. In primed cells most of the increased production of reactive oxygen species induced by fMLP is located intracellularly, whereas, an increased extracellular release of reactive oxygen species occurs during phagocytosis. The fact that primed cells can both produce and, under certain conditions, release increased amounts of hydrogen peroxide raises the question of whether the primed cell is a friend or a foe in the inflammatory reaction.</p>
  • Forastiere, Francesco (författare)
  • Epidemiologic studies of occupational and environmental exposures and cancer of the lung
  • 1994
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>In order to study the importance of some less well-known occupational exposures and environmental factors in lung cancer etiology, a series of investigations were conducted in the Latium region of Italy, which includes the city of Rome. Five historical cohort studies were carried out on various occupational groups: power plant workers and merchant seamen with potential exposure to asbestos occupations with exposure to silica dust (silicotics receiving a disability compensation), and occupations withexposure to sulphuric acid mist (soap production workers) and to engine exhaust (taxi drivers). In addition, a case-control study evaluated lung cancer risk among ceramic workers exposed to silica dust, and a correlation study compared lung cancer mortality rates in areas with distinct geological features as a proxy of radon exposure in dwellings. Finally, time trends and geographical differences in lung cancer mortality rates in Italy not due to active smoking (background rates) were estimated to obtain an overall view of the aggregate effect of other factors than active smoking.</p><p>More or less clearly increased risks of lung cancer mortality were observed in the cohorts of power plant workers (SMR=ol. 8, 95% cr~D.77-3.5;9D~ cr~o.ss-3.2), and merchant seamen (SMR~1.7, 95~ CI=l.l-2. 5) 1 probably mainly due to asbestos. An excess lung cancer risk was detected among ceramic workers (OR=2. 0, 95% CI=l.l-3.5); those ceramic workers with silicosis showed an even higher relative risk (0R=3. 9, 95% CI=l. 8-8.3) . Subjects receiving a disability pension for silicosis in the region were also found to have an increased risk of lung cancer (MOR=1.5; 95% CI=l.l-1.9). There was a suggestion of excess risk of lung cancer among workers in the production of soap (SMR=1.7; 95%CI~D.55-3.9; 90~ CI~0.73-3.6), although the limited size of the study precludes any definitive conclusion. Taxi drivers in Rome also appeared to have a slightly increased risk of lung cancer (SMR~1.2, 95~ CI~D.97-1.5), especially those enrolled more recently (SMR~1.4, 95~ CI~l.02-1.9)</p><p>After adjustment for smoking and urbanization, the ecologic study showed a 20% increase in mortality rates for lung cancer in an area with a higher level of background radiation. Indoor radon exposure may be suggested as a potentially important risk factor for lung cancer in that area.</p><p>When differences of time and place in lung cancer death rates not attributable to active smoking were studied, all calculations indicated that the estimated background rates increased in Italy from the period 1956-58 to the period 1987-1989, especially in males. Higher background rates were observed in heavily urbanized areas than in rural areas.</p><p>The overwhelming role in cigarette smoking is well recognized but various environmental factors also play an important role in causing lung cancer. These factors should not be neglected in public health efforts to reduce the risk of lung cancer, especially as they may at times be easier to reduce or eliminate than smoking.</p>
  • Fällman, Maria (författare)
  • Complement receptor-mediated signal transduction in human neutrophils : A role for protein kinase C in the phagocytic process
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The neutrophil granulocyte comprises the first line of human defense against invading microorganisms. A versatile motile machinery enables the cell to migrate to the inflammatory site and there engulf and destroy the pathogens by phagocytosis. Engulfment is facilitated by opsonization of the microbes with C3b or C3bi complement fragments or with immunoglobulins, proteins which respectively bind to complement receptors (CRs) and Fe receptors on the neutrophil surface. The aim of the present thesis was to investigate the transmembrane signaling events involved in receptor-mediated engulfment.</p> <p>Experimentially induced inhibition of the phagocytic capacity of human neutrophils could be reversed by pretrcating the cells with protein kinase C (PKC)-activating agents such as PMA and a synthetic diglyceride. This indirectly suggests an important role for PKC in the process of engulfment. Presentation of opsonized yeast particles to neutrophils stimulated the phosphoinositide signaling pathway, resulting in an accumulation of Ins(1,4,5)P3 (IP3) and diglyceride (DG; the endogenous activator of PKC) with a time kinetic correlating that of the cellular uptake of the particles. However, in calcium-depleted neutrophils, formation of IP3 was totally abolished during phagocytosis of complement-opsonized yeast particles, thereby excluding this signal as a regulator of the engulfment process. DG, on the other hand, was still produced in these cells, suggesting a source other than phosphatidylinositols for the generation of this second messenger. Further studies revealed that a major part of CR-mediated DG formation originated from phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine (PC). The presence of DG suggested a subsequent activation of PKC, which was confirmed by the demonstration of CR-mediated phosphorylation of a well-known PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS). Moreover, the activity of PLD was shown to be regulated by PKC, which stimulated the production of its own activator by enhancing the activity of the lipase: PKC should thereby be able to maintain its own activity.Furthermore, we could also show that both CRI and CR3 can mediate PLO activation and that the degree of this activation is potentiated by PMA pretreatment and dependent on the fonn of ligand presentation. In conclusion, CR-mediated phagocytosis is associated with PLDmediated hydrolysis of PC and stimulation of PKC, the activity of the latter enzyme appears to be an important regulatory event in the engulfment process.</p>
  • Gadegaard Jensen, Anders (författare)
  • Clinical and laboratory studies on propofol
  • 1993
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Patients undergoing major abdominal surgery were randomly given total intravenous anaesthesia based on propofol and fentanyl, anaesthesia based on propofol, fentanyl and nitrous oxide or anaesthesia based on isoflurane and fentanyl. Postoperative atelectasis demonstrated by computed tomography of the chest was found to a similar extent and a similar decrease in arterial oxygen pressure was seen in the groups. No correlation was seen between the size of atelectasis and postoperative oxygen pressure. Cardiovascular stability was equally well maintained during surgery, but the patients anaesthetized with propofol needed more ephedrine and glycopyrrolate to achieve stability. In all groups the Acute Physiology Score was normal by day I (range 1-7). A similar impairment of bowel function after operation was found, with passage of gas day 3 ( 1-6) and tolerance of enteral intake day 5 (1-10). Hospital stay 11 (6-45) days and incidence of complications were unaffected by anaesthetic technique. Early recovery was similar in the three groups, but patients anaesthetized with propofol reported fewer symptoms, better subjective control and a higher degree of socially orientation than patients anaesthetized with isoflurane. On the whole, the advantages with propofol compared to isoflurane were small, and the addition of nitrous oxide to propofol had no influence on. the results.</p><p>Laboratory tests on human leucocytes, cultured human glial cells and rat glial cells and neurons were performed with propofol in concentrations between 0.3 ~g·ml" and 50 ~g·ml" (1.7 to 280 ~M). Clinically relevant concentrations of propofol decreased random and chemotactic locomotion of leucocytes in an agarose assay. Concentration dependent and reversible effects of propofol were found on the actin distribution of the cytoskeleton in cultured cells. The maximal effect was seen after 20 min of incubation. Using a single cell microfluorometric method with Fura2 an increase in cytosolic free calcium in rat neurons was seen immediately after the addition of propofol, lasting 128±39 seconds and thereafter returning to normal. This effect was dual, 60-7 5% of the increase came from the extracellular buffer and the remaining part from intracellular stores. A rise in intracellular calcium can lead to changes in the cytoskeleton and to hyperpolarization of a neuron.</p>
  • Gasslander, Thomas, 1952- (författare)
  • Long-term effects of cholecystokinin on exocrine and endocrine pancreas
  • 1991
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The gastrointestinal hormone cholecystokinin (CCK) is known to be oneof the most potent stimulators of pancreatic growth. CCK is alsosuggested to be an initiator and/or promotor of pancreatic carcinogenesis. This study was undertaken to elucidate the effects oflong-term stimulation with exogenous and endogenous CCK andexogenous secretin on exocrtne and endocrine pancreatic cell proliferation (in rats and mice) and on . endocrine (B-cell) function (inrats). Cell kinetics were studied autoradiographically by means of 3H-thymidine labeling of DNA synthesizing cells and endogenous increasein plasma CCK level was induced by surgical pancreatico-biliary diversion (PBD).</p> <p>The study showed that long-term stimulation with the CCK analogue cerulein (in mice) as well as endogenously induced hyperCCKemia (in rats) induced pancreatic hyperplasia. The proliferative response was as high, or even higher, in the ductal and centroacinar cell populations than in the acinar one, which traditionally is regarded as the target forCCK. The cells adapt to the continuous CCK stimulation with a decrease in proliferative activity to control level after 14-20 days. Cerulein seems to induce early changes in the centroacinar cell region with signs of transition of cells from acinar to centroacinar position. Secretin, which has the ductal cells as its main target cell, had no growth stimulating effect on any of the studied cell types. Long-term endogenous CCK stimulation does not affect the proliferation of cells in the islands of Langerhans, nor affect the insulin secretory response or the glucose elimination following intravenous glucose loading. The results of the study are of special interest as human pancreatic carcinoma is considered to be ductal and as there are suggestions of early changes in the centroacinar · region in experimental pancreatic carcinogenesis. Funhermore, the PBD model was found to be suitable for studies on longterm CCK effects, as the pancreatic growth response following PBD was exclusively caused by the increased plasma CCK level.</p>
  • Gauffin, Håkan (författare)
  • Knee and ankle kinesiology and joint instability
  • 1991
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>This study, comprising 7 separate papers, is concerned with the additional information supplied by a kinesiological approach for evaluation of patients with instability due to old ligamenta us injury to the knee or ankle joint. This approach required development of new methods for kinesiological analysis.</p> <p>Impaired performance in patients with old anterior cruciate ligament (ACL) rupture was mainly found in tests which greatly stress the knee joint, ie figure-of-eight running and one-legged jump for distance.</p> <p>A scaling model approach was constructed and found appropriate in evaluating knee and ankle function in patients with ligarnentous injuries.</p> <p>A dynamic, two-dimensional, biomechanical model was developed and implemented in a motion analysis system together with a force plate and EMG. This model was found useful for evaluation of kinematics, kinetics and muscular activation patterns at the ankle, knee and hip joints during functional movements such as walking and jumping.</p> <p>A movement analysis could reveal adapted movement- and muscular activation patterns for the ACL-deficient knee compared to the noninjured at touch down at one-legged jump. An internal knee model disclosed a simultaneous decrease in sagittal shear load which was interpreted as an adaptation to avoid increased intrinsic joint movements or gross subluxations.</p> <p>Unilateral injury to the lateral ligaments of the ankle is related to both ipsi- and contralateral functional alterations. There is a risk of underestimating the impairment of the injured joint in a function test using the noninjured side as a reference.</p> <p>A perturbation device was construcred and found useful for the analysis of postural strategies, reaction latencies and ankle joint function during single limb stance. The ankle joints were found to be of primary concern for postural corrections to retain equilibrium in single limb stance.</p> <p>A quasi static, three-dimensional ankle model was developed and implemented in a motion analysis system which made possible study of ankle joint function, load and instability. Different motor patterns were found for the functionally unstable foot compared to the stable in single limb stance.</p> <p></p>
  • Good, Lars, 1953- (författare)
  • Anterior cruciate ligament reconstruction : Anatomic and biomechanical considerations of graft placement and fixation
  • 1993
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>This study, comprising 7 separate papers, is concerned with the mechanical causes of graft failure after intraarticular reconstruction of the anterior cruciate ligament (ACL). The study is predominantly experimental in design, but a clinical follow-up is also included to test a causal hypothesis of secondary graft elongation.</p><p>Fixations of synthetic ACL substitutes with ligament staples had low security and the maximum tolerance loads were in parity with forces generated during daily activities, while screw fixations of looped ligaments had higher load to failure than a normal ACL.</p><p>A stenosis, caused by osteophyte formation, was found at the intercondylar notch less than 2 years after an ACL tear, strongly suggesting impingement and wear as a possible mechanism of ACL substitute failure. The intercondylar notch was also found to be narrowed in patients with an acute tear of the ACL compared to a normal control group, thus implying causality.</p><p>A standardized technique of graft placement, using a guide to aid bone drilling, was found more accurate and reproducible in achieving desired graft insertions compared to freehand drilling. This was evaluated by a new method for detennining the graft insertion locations on the femur and tibia, using a ratio related to the sagittal depth of the condyles.</p><p>The ability to restore knee kinematics from an ACL deficient state, was evaluated for a drill guided graft route and an over-the-top route. The only effect of both methods, using a dacron graft tensioned in full extension, was restoring or partially restoring the increased anterior -posterior translation.</p><p>A good in vitro and in vivo correlation was found between the patterns of change in dynamic fixation distance, as measured intraoperatively with an isometer, and tension in the fixed ACL substitute. The isometry measurement could not predict the magnitude of the frnal tension due to the biological variability in soft tissue compliance.</p><p>Sagittal knee stability was measured at regular intervals for 2 years on patients who had an intraarticular ACL reconstruction with a patellar tendon substitute. Increasing anterior-posterior displacement was found for all patients as a group, and more for patients with an anterior femoralligament insertion location.</p><p>A standardized treatment including aided bone drilling, notch plasty, isometry measurement, and restricted postoperative rehabilitation is recommended.</p>
  • Grodzinsky, Ewa, 1958- (författare)
  • Serological markers in subclinical and clinical gluten enteropathy
  • 1994
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>An enzyme-linked immunosorbent assay (ELISA) has been developed for the measurement of anti-gliadin antibodies (AGA), thereby providing a practical and cheap assay for use in the diagnosis of coeliac disease (CD). Since gliadin is a common food antigen for most people, a large group of apparently healthy blood donors (n=l866) was analysed, as well as children and adults with symptoms more or less suggesting CD. The effects of various cut-offvalues on the sensitivity, specificity and predictive value (PV) of the test were calculated, both alone and together with anti-endomysium antibodies (EMA). A high prevalence value, of at least 1/256 (7!1866), for gluten enteropathy (GE) was found in the blood donor population. Moreover, a high frequency of CD among fanners with diffuse symptoms, conceivably due to a high exposure to gluten by inhalation, was also observed. It was impossible to combine high sensitivity with high specificity for both IgA- and IgG AGA, and vice versa, in adults. A significant increase in the mean lgA AGA level with age was seen when the blood donors were divided into age groups. A positive PV of 18-25% was found for IgA-AGA, depending on how-the cut-off value was defined. For IgG-AGA the positive PV was 0% (0/35) among asymptomatic subjects. IgA-EMA yielded both high specificity and a high positive PV, but a lower sensitivity than IgA-AGA, especially in children younger than 2 years, with signs of CD. When screening for GE in a population with expected low prevalence, measurement of IgA-AGA is suggested as a primary test because of fairly good sensitivity, technical simplicity, and low cost. Sera found to be positive are then re tested with IgA-EMA, which gives a positive PV close to 100%. For populations with a moderate or high expected prevalence for CD, our results indicate that different tests should be used depending on the age of the population studied. In younger children ( &lt; 2 years old) lgA-AGA yielded a high sensitivity (lOO%) and a high specificity (86%). fu older children (&gt; 2 years old) and adults the use of IgA-EMA seems more suitable, because of the high specificity (99-100%) and positive PV (95-100% ). Since, however, the negative PV was not 100%, a negative test result does not exclude CD.</p>
  • Grönberg, Anders (författare)
  • Reactive arthritis : The human antibody responce elicited by <em>Yersinia enterocolitica</em> and <em>Clamydia trachomatis</em>
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>A central issue in the pathogenesis of reactive arthritis (ReA) is whether or not individuals developing arthritis have an aberrant immune response to individual antigens of potential triggering microorganisms. Although evidence exists that Yersinia and Chlamydia are two agents that precipitate ReA it has not been shown that these pathogens share common antigens. To address this hypothesis, the antibody responses in individuals with ReA associated with Yersinia or Chlamydia have been analysed.</p><p>Results reveal that 60% of patients with ReA following urogenital infectionhave antibodies to C. trachomatis, compared to 33% of patients withankylosing spondylitis and 19% of healthy blood donors.</p><p>All patients infected with Y. enterocolitica developed IgG and IgA immuneresponses against a limited number of antigens, which can be detected within weeks of the onset of symptoms. The immune response to most of these antigens persisted throughout the follow-up period (the longest being 993 days). The IgG response was partly directed against different antigens not involved in the IgA response. There were substantial differencies between patient sera as regards anti genic specificity patterns. Individual variations were more pronounced than any putative similarities among patients with ReA or uncomplicated enterocolitis (UEC).</p><p>Sera from patients with Y. enterocolitica-triggered ReA with or withoutantibodies to Chlamydia and sera from patients with UEC caused by Y. enterocolitica were analysed for cross-reactions with Salmonella typhimurium and C. trachomatis, representing two arthritis-associated bacteria. It was found that three antigens were restricted to arthritis associated organisms. Affinity purification suggested that one antigen of 74 kDa was recognized in Yersinia-, Salmonella-, and Chlamydia antigen preparations.</p><p>A standardized method for quantitative Western blot analysis, using ascanning and image-processing system, was developed. Using this system it was found that the degree of antibody response could vary significantly between different runs. The amount of antigen transferred was found to be the key factor affecting the interpretation of the antibody response.</p>
  • Gunnarsson, Lars-Gunnar (författare)
  • On the occurrence and possible causes of motor neuron disease in Sweden
  • 1992
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>A series of investigations have been performed to study secular trends of motor neuron disease (MND) morbidity and mortality in Sweden, to identify time and/or space clusters, if any, and to uncover risk factors. The occurrence of the disease was estimated from incidence, prevalence and mortality rates, and the strength of various determinants was evaluated by means of the case-control approach, using population controls. The studies comprised different periods of time between 1961 and 1990.</p><p>The mortality rate from MND in Sweden, for both genders taken together, doubled from 1961 to 1985, reaching 2.5 per 100,000 person-years, and the incidence rates were of a similar magnitude. The age-specific mortality rates peaked at 70 to 75 years of age. Regarding separate birth cohorts the peak was less clear, however, and the mortality rates tended to increase continuously with advancing age. An epidemic of MND was identified in the county of Skaraborg during the period 1973-1984, when three times as many males as expected had onset of MND, especially involving the farm-working population. In the community surveys involving the counties of Viirmland and Skaraborg the 50% survival rate was slightly more than two years.</p><p>Among males high adjusted odds ratios were obtained for electricity work (0R=6.7, 95% Cl 1.0-32.1), welding (0R=3.7, 95% Cl 1.1-13.0) and exposure to impregnating agents (0R=3.5, 95% Cl 0.9-13.1). Heredity with regard to a neurodegenerative disease and/or thyroid disease yielded OR=2.1, 95% Cl 1.0-4.3. The highest odds ratio was found for the combination of such heredity, exposure to solvents and male gender (0R=l5.6, 95% Cl 2.8-87.0).</p><p>In sum, an increase in MND seems to have taken place during the last few decades. The regional epidemic especially among males in agricultural work, the high risk estimates regarding some occupational exposures of mainly chemical nature, and the interaction with heredity, indicate that environmental factors might play a role in the pathogenesis of MND, and that a subpopulation might be particularly susceptible.</p>
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